How is Bone Fragility Inherited? The Effects of Gender and Parental Genotype

Background

The ability of structures, like bone, to resist fracturing depends on the underlying morphology and tissue-level mechanical properties [1]; consequently, properties like strength and toughness will depend on multiple skeletal traits. Because each trait is genetically complex [2], not all traits will necessarily be inherited in the same manner. Variation in the inheritance pattern among traits would, based on mechanical principals, result in a complex relationship between the fracture resistance of the parents and the offspring. Given that females show a high fracture incidence, we asked, "Do females inherit mechanically relevant bone traits differently than males?"

Materials and Method

Reciprocal crosses were generated between 3 inbred mouse strains - A/J, C57BL/6J (B6), C3H/HeJ (C3H) - to produce 12 F1 hybrid strains (6 reciprocal crosses x 2 genders; n=6-10/genotype). Morphological, compositional, and biomechanical properties were assessed for the femurs from 16-week hybrids. Z-scores were determined for each trait and property to compare males and females and to compute dominance.

Results

Adult hybrid trait and property values were generally intermediate between the parents. However, dominance for each property and trait varied significantly among the hybrids, between reciprocal crosses, and between genders. This suggested that the genes which influence each trait and property do not always act in a simple additive manner and may act differently for each cross and for males and females. Although the mechanical properties of the hybrids could not be accurately predicted by knowing the mechanical properties of the parents, regression analyses revealed that the dominance values for the mechanical properties correlated with those of the underlying bone traits in a manner that was consistent with structure-function relationships.

Conclusions

This study provided new insight into the way a complex mechanical event like fracture is inherited. The data indicated that inheritance of mechanically relevant bone traits depends on gender, the genotype of the parental strains, and is subject to maternal effects. Although males and females inherit skeletal traits differently [3], they showed nearly identical structure-function relationships. This implies that it should be possible to predict the heritability of fracture risk for either gender based on knowledge of bone structure-function relationships, the identity of mechanically relevant bone traits, and the assessment of these particular traits in situ.

References

1. van der Meulen MC, Jepsen KJ, Mikic B: Understanding bone strength: size isn't everything.

   Bone 2001, 29(2):101-104. PubMed Abstract | Publisher Full Text

2. Recker RR, Deng HW: Role of genetics in osteoporosis.

   Endocrine 2002, 17(1):55-66. PubMed Abstract | Publisher Full Text

3. Orwoll ES, Belknap JK, Klein RF: Gender specificity in the genetic determinants of peak bone mass.

   J Bone Miner Res 2001, 16(11):1962-1971. PubMed Abstract | Publisher Full Text

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